Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio
Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio
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DOI：
10.1038/emboj.2010.211
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发表时间：
2010-10-06
期刊：
影响因子：
11.4
通讯作者：
De Strooper, Bart
中科院分区：
文献类型：
--
作者：
Kuperstein, Irina;Broersen, Kerensa;De Strooper, Bart
阿尔茨海默病的淀粉样肽A β（40）和A β（42）被认为对疾病过程有不同的贡献。虽然A β（42）似乎比A β（40）更具致病性，但其原因尚不清楚。我们在这里表明，A β（42）：A β（40）比例的微小变化显着影响A β混合物的生物物理和生物学特性，反映在它们的聚集动力学，所产生的淀粉样纤维的形态和体外和体内测试的突触功能。A β（42）：A β（40）比率的轻微增加使具有中间构象的毒性低聚物种类稳定。这些A β物质的初始毒性影响本质上是突触性的，但这可以扩散到细胞中，导致神经元细胞死亡。A β肽的相对比例比肽的绝对量对于诱导神经毒性构象更重要，这一事实对于抗淀粉样蛋白治疗具有重要意义。我们的工作还表明了有毒和无毒中间体之间平衡的动态性质。The EMBO Journal（2010）29，3408-3420. doi：10.1038/doj.2010.211; 2010年9月3日在线发布
The amyloid peptides A beta(40) and A beta(42) of Alzheimer's disease are thought to contribute differentially to the disease process. Although A beta(42) seems more pathogenic than A beta(40), the reason for this is not well understood. We show here that small alterations in the A beta(42):A beta(40) ratio dramatically affect the biophysical and biological properties of the A beta mixtures reflected in their aggregation kinetics, the morphology of the resulting amyloid fibrils and synaptic function tested in vitro and in vivo. A minor increase in the A beta(42):A beta(40) ratio stabilizes toxic oligomeric species with intermediate conformations. The initial toxic impact of these A beta species is synaptic in nature, but this can spread into the cells leading to neuronal cell death. The fact that the relative ratio of A beta peptides is more crucial than the absolute amounts of peptides for the induction of neurotoxic conformations has important implications for anti-amyloid therapy. Our work also suggests the dynamic nature of the equilibrium between toxic and non-toxic intermediates. The EMBO Journal (2010) 29, 3408-3420. doi:10.1038/emboj.2010.211; Published online 3 September 2010